Not applicable.
1. Field of the Invention
The present invention relates to the association between the serotonin transporter (HTT) gene and serum cholesterol levels, heart disease and longevity.
2. Description of the Related Art
The full citations of the publications referred to herein are found at the end of the specification. The contents of the references are incorporated herein by reference.
Low cholesterol levels have been reported to be associated with the development of depression and violent death by suicide, especially in the elderly (1-5). This occurs both in subjects in the general population and subjects whose cholesterol levels have been lowered by medication. Several possible mechanisms for these phenomena have been suggested including a decrease in serotonin levels (3, 6) or a decrease in the number of membrane serotonin receptors or transporters due to the effect of low cholesterol on membrane fluidity (6). A link between serotonin levels and cholesterol was supported by studies in monkeys showing that those with cholesterol levels altered by diet showed a positive correlation between plasma cholesterol level and central serotonergic activity (7, 8). By contrast, a study by Fernstron, et al. (9) found no significant differences in tryptophan, serotonin or 5-HIAA concentrations in several brain regions in gerbils with a wide range of diet induced variations in cholesterol level.
Steegmans, et al. (10) reported a significant decrease in plasma serotonin, but not platelet serotonin, in 100 men in the general population with a demonstrated long term (3 years) cholesterol level below the fifth percentile compared to 100 control men with cholesterol levels in the 35th to 75th percentile. Smith and Betteridge (11) observed a significant negative correlation between platelet serotonin and cholesterol levels in subjects with hypercholesterolemia and controls (r for both combined=xe2x88x920.48, pxe2x89xa60.005). In the hypercholesterolemic subjects there was a significant positive correlation with high-density lipoprotein (HDL) (r=0.79, p=0.001). They concluded there was a significant relationship between circulating cholesterol and platelet serotonin and that a serotonin uptake (transporter) mechanism was involved. Others have suggested the apparent association between low cholesterol and depression could be due to the fact that both were related to a third confounding factor, such as general poor health (12).
The observations that low cholesterol levels induced by medication or diet can be associated with depression suggest that environmental factors are involved and that the low cholesterol was the primary event while the altered serotonin levels were secondary. However, the observation that low cholesterol levels in individuals in the general population can be associated with low serotonin levels and depression is compatible with the possibility that in some cases genetic factors could be responsible for either the low cholesterol, the depression, or both. The fact that elderly subjects are often involved suggests that some variables may be related to age. There is also a well documented association between depression and cardiovascular disease in general (13).
In one aspect, the present invention relates to a method for screening a subject to determine whether such subject is at increased risk for developing cardiovascular disease, said method comprising determining the subject""s genotype with respect to the serotonin transport (HTT) gene, wherein an LS heterozygote for the HTTLPR insertion/deletion polymorphism at the promoter region of the HTT gene has an increased risk for developing said disease.
In another aspect, the present invention relates to a method for screening a subject to determine whether such subject is a candidate for a therapy using a drug which prevents or treats a cardiovascular disease associated with excessive production of the serotonin transport protein, said method comprising determining the subject""s genotype with respect to the serotonin transport (HTT) gene, wherein an LS heterozygote for the HTTLPR insertion/deletion polymorphism at the promoter region of the HTT gene is a candidate for such therapy.
In another aspect, the present invention provides a method for screening a subject to determine the potential longevity of such subject, said method comprising determining the subject""s genotype with respect to the serotonin transport (HTT) gene, wherein an SS homozygote for the HTTLPR insertion/deletion polymorphism at the promoter region of the HTT gene has a greater probability of survival past eighty years of age.
In another aspect, the present invention relates to a method for treating a patient at increased risk for developing cardiovascular disease due to the patient being LS heterozygous for the HTTLPR insertion/deletion polymorphism at the promoter region of the serotonin transport (HTT) gene, said method comprising administering to said patient an effective amount of a material which diminishes the effect of the serotonin transporter protein.
In another aspect, the present invention relates to a method for identifying materials that can be used in the treatment of a patient at increased risk for developing cardiovascular disease due to the patient being LS heterozygous for the HTTLPR insertion/deletion polymorphism at the promoter region of the serotonin transport (HTT) gene, said method comprising determining whether the material is capable of diminishing the effect of the serotonin transporter protein.
In another aspect, the present invention relates to a pharmaceutical composition which comprises
a) an effective amount of a material which is capable of diminishing the effect of the serotonin transporter protein in a patient being LS heterozygous for the HTTLPR insertion/deletion polymorphism at the promoter region of the serotonin transport (HTT) gene; and
b) a pharmaceutically acceptable carrier.
In another aspect, the present invention relates to a kit suitable for screening a subject to determine whether such subject is at increased risk for developing cardiovascular disease, said kit comprising
a) means for determining the subject""s genotype with respect to the insertion/deletion polymorphism at the promoter region of the serotonin transport gene;
b) suitable packaging material; and optionally
c) instructional material for use of said kit.